The morphological events forming the tooth are sensitive to genetic and environmental perturbations resulting in a high incidence of congenital malformations. Furthermore, tooth decay is by far the most common chronic childhood disease, with a 5-fold greater incidence than asthma, and a 7-fold greater incidence than hay fever. Tooth decay is also a major cause of tooth loss in adults;approximately one-third of adults over the age of 65 in this country have no natural teeth at all. Thus, there is a great need to understand the molecular mechanisms regulating tooth formation and repair in detail. Recent advances in human and mouse molecular genetics have illuminated key events of early tooth patterning and morphogenesis. Because these early developmental events share the same molecular networks with regenerating tissues, it seems likely that these advances in the basic science of tooth development will lead to stem cell therapies for tooth repair. The objective of this proposal is to elucidate the molecular mechanisms underlying the action of Ctip2 during incisor development. This objective will be accomplished in the context of our central hypothesis: Ctip2 regulates a key transcriptional network(s) responsible for ameloblast maturation during incisor development. The goals for this project are to identify component proteins of Ctip2 complexes in the developing oral cavity (Aim 1), and to elucidate the mechanistic basis for regulation of target gene expression by Ctip2 during incisor development (Aim 2). After completion of this research, we expect that we will have defined Ctip2-controlled genetic and regulatory networks, which directly impact cell specification in the developing incisor. Our studies will have significant, positive effects on human health because these outcomes will provide an enhanced understanding of gene regulation during incisor development and amelogenesis, the latter of which may lead to development of more efficacious treatment paradigms for ex vivo ameloblast growth and ultimately enamel restoration, which is not currently possible. PUBLIC HEALTH RELEVANCE: Tooth development is sensitive to genetic and environmental perturbations, which lead to a high incidence of dental malformations. There is a great need to understand the molecular mechanisms regulating tooth development and repair. Recent advances in human and mouse molecular genetics have illuminated key events of tooth patterning and morphogenesis, and have lead to potential gene therapies for cell lineage regeneration and tooth repair. The objective of our proposed studies is to define the role of Ctip2/Bcl11b in incisor development.